A brief history of antimicrobial resistance (AMR)

Until the 20th Century, influenza and pneumonia, tuberculosis, and enteric infections were among the top three causes of death. The average life expectancy of an adult in Western Europe was less than 50 years, and 2% of children failed to live beyond 5 years of age due to deaths caused mostly by infectious diseases.

Industrialization and growing wealth during the 19th century brought improvements in drinking water and sanitation for many countries, leading to reductions in communicable enteric infections and dramatic improvements in life expectancy. By the early 20th century, advances in immunization further reduced mortality as vaccines for pertussis, diptheria, yellow fever and tuberculosis were introduced. However, common bacterial infections remained a serious medical threat. Streptococcal throat infections were sometimes fatal, ear infections could progress to deafness, mastoiditis or meningitis, and even minor surgeries were associated wit life-threatening infections. Maternal mortality during childbirth approached 1%.

Antibacterial resistance emerged with bacteria on earth approximately 2-2.5 billion years ago. In contrast, the first humans are believed to have existed around 2 million years ago. Therefore, it cannot be said that humans are the cause of antimicrobial resistance.Antibiotic resistance pre-dates the use of antibiotics in medicine. Indeed, antibiotic use is inevitable. Any use of an an antibiotic will eventually select for antimicrobial resistance.

The first recorded use of antimicrobial -like substances was by the early Egyptians, Greeks, and Chinese, who used natural products with antimicrobial activity for millennia to treat wounds and infections, even if the causes of these diseases were unknown until the 19th and 20th century.

The microbiologist and immunologist Paul Ehrlich (1854-1915) is credited with the discovery and first medical application of a synthetic antibiotic arsphenamine (Salvarsan) for the treatment of a bacterial infection-syphilis. Yet it was the serendipitous discovery of penicillin in 1928 by Alexander Fleming, and its subsequent purification of the drug in quantities needed for clinical testing by Drs. Florey and Chain in the 1930s, that initiated the true start of the modern antibiotic era. Interestingly, the term antibiotic was actually coined by Selman Waksman, a biochemist and microbiologist who discovered the first effective treatment for tuberculosis, streptomycin, and was awarded the Nobel prize in 1952.

Alexander Fleming was among the first physicians to caution about the risks of resistance to penicillin if used too little or for a too short of period during treatment. In his Nobel Prize acceptance speech, Dr. Fleming noted:

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

-Sir Alexander Fleming, Nobel Prize Lecture, December 11, 1945

By 1947, Fleming’s predictions had come true as the first cases of penicillin resistance were already being reported. Thus began the modern era’s “arms race” between new antibiotic discovery and increasing antimicrobial resistance.

Initially, antibiotic discovery seemed to keep pace with resistance as a host of new chemical classes were developed and introduced in the 1950s-1980’s. For the first half of the century, the repeated and successful response to emerging resistance was to discover new antibiotics.¹ Yet by the 1980’s, the discovery of new agents began to slow and this strategy began to fail.. The latest discovery of a new antibiotic class that has reached the market was in 1987. Since then, there has been a lack of innovation in the field, and today there are few novel antibiotic classes in the drug pipeline. In Module 2 we will examine the scientific challenges and market forces that have made new antibiotic discovery increasingly difficult and how access to newer antibiotics is limited in many parts of the world.

Once antibiotic resistance develops, it can spread from one colonised patient to another patient if appropriate hygienic precautions (e.g., hand hygiene, isolation) are not followed. The risk of resistant bacteria spreading is enhanced in crowded environments, especially when people in the surrounding area are receiving antibiotics - a common scenario in hospitals especially in wards of critically-ill patients.

The consequences of faltering antibiotic discovery are now being felt worldwide as more and more bacterial infections are becoming harder to treat. Especially worrisome is the lack of antibiotics against common Gram-negative bacteria (i.e. Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Acinetobacter baumannii) that are increasingly resistant to all but last-line antibiotics. The rapid global spread of multi- and pan-resistant bacteria, also known in the lay press as “superbugs,” can cause infections that are not treatable with existing antibiotics.

Click this link to watch a YOUTUBE video of how quickly Escherichia coli and develop resistance to ciprofloxacin.

Global response to antimicrobial resistance

Recognizing the growing global threat of antibiotic resistance (AMR) on human health but also the economy and human development, The World Health Organization (WHO) and The Organisation for Animal Health (OIE) developed in 2001 a Global Plan for Containment of Antimicrobial Resistance that subsequently led to a Global Action Plan for AMR in 2017 and more recently a “Call to Action on Antimicrobial Resistance” in 2021. The plan outlines 21 strategies and 5 strategic objectives action plans that should be implemented in member states to address AMR. These include:

1. Improvements in the awareness and understanding of antimicrobial resistance through effective communication, education and training
2. Strengthening of knowledge and evidence base of AMR through surveillance and research
3. Reductions in the incidence of infection through effective sanitation, hygiene and infection prevention measures
4. Optimization the use of antimicrobial medicines in human and animal health
5. Development of an economic case for sustainable investment in AMR research that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions

The WHO also proposed a Priority Pathogen List for research and development of new antibiotics and established a global antimicrobial use and surveillance program. This list includes bacterial pathogens that are considered to be be the biggest threat to human health in addition to Mycobacterium tuberculosis. The WHO list breaks down pathogens into three groups:

These pathogens may exhibit multi-drug resistance (MDR), extensive drug resistance (XDR) or pan-drug resistance (PDR).² Difficult-to-treat resistance (DTR) is a newer definition used to define isolate resistance patterns that require the use of less-effective or more toxic “reserve” antibiotics- e.g., Acinetobacter baumanii susceptible only to colistin and tobramycin.³

Currently, both the WHO and OIE have also developed lists of antibiotics that are considered of “critical importance” for human and animal medicine. These lists help establish priorities for antimicrobial resistance surveillance and new drug development.

What are the drivers of antimicrobial resistance?

AMR is a natural phenomenon. Most antimicrobial drugs are naturally produced by micro-organisms, including environmental fungi and saprophytic bacteria, or are synthetic modifications of these natural products, with only a few drugs (e.g., sulphonamides and fluoroquinolones) being wholly synthetic. Yet AMR selection is accelerated by antimicrobial exposure in health care, agriculture, and the environment. Further transmission is affected by standards of infection control in healthcare settings, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration.

Antimicrobials are among the most commonly prescribed drugs used in human medicine, yet up to 50% of all antimicrobials prescribed to people are considered unnecessary. This use, misuse, or overuse of antimicrobial drugs is considered to be a major driving force towards antimicrobial resistance. Globally, the use of antimicrobials is accelerating worldwide, particularly in LMICs, as antimicrobials become readily accessible and affordable. The use of WHO Watch antibiotics increased 90.0% worldwide and 165% in LMICs between 2000 and 2015.

In medicine, the concentration of antibiotic prescribing might be highest in inpatient settings, with 30–40% of patients on antibiotics in European hospitals. However, the overall highest quantity of antimicrobial consumption is highest in the community setting.

Yet, more antimicrobials are used in food production than in human beings, with marked national differences in the number of antimicrobial drugs used in food producing animals. It has been estimated that 73% of all antibiotic use per by weight is for food production in animal.⁴Various studies have shown that antimicrobial resistance has, at least in part, emerged as a result of the selective pressure exerted by antimicrobial use outside of human medicine, namely in veterinary medicine, food-animal and fish production, and agriculture. Therefore to effectively AMR, a multifaceted or ONE-HEALTH approach is required.

AMR in Low-Middle Income Countries (LMICs)

AMR is a global problem, but its prevalence across the globe varies with antibiotic consumption, access to clean water and adequate sanitation, vaccination coverage, and access to quality healthcare. The latest WHO report, based on AMR data from 66 countries, illustrates an alarming picture of the global status of AMR as an increasing number of countries are now reporting high rates of resistance among antimicrobials used to treat common infections.

There are considerable knowledge gaps regarding AMR prevalence in LMICs that lack clinical and laboratory capacity and surveillance infrastructure. A systematic review of 144 16 studies across Africa lacked AMR data for approximately 40% of the African countries. In the Asia and Pacific region, South East Asia is estimated to have the highest risk of AMR emergence and spread, with the highly transferable New Delhi metallo-β-lactamase-1 (NDM-1) as an example. Furthermore, China and India alone accounted for more than one-third of the global incidence of 17 multidrug-resistant (MDR) tuberculosis.⁶

COVID-19 has focused global attention on the inequitable access to the tools needed to control the pandemic, with high-income countries (HICs) and low- and middle-income countries (LMICs) at opposite ends of the scale. In the case of antibiotic resistance, a pandemic projected to cause four times more deaths per year than occurred from COVID-19 during 2020, inequity between HICs and LMICs is a major challenge:⁷

LMICs are particularly susceptible to the emergence and rapid spread of AMR for several reasons:

• High population density
• Lack of access to clean water, suboptimal sewage systems, poor sanitation
• Poor healthcare infection control practices
• Increasing consumption of antimicrobials in humans
• Availability and distribution of poor-quality (counterfeit) medicines
• Lack of regulation on antimicrobial use in farming, and pharmaceutical industry pollution

The health and economic impact of AMR is also more severe and longer lasting in LMICs versus HICs. AMR is generally associated with:

• Increased mortality and health costs

• Antibiotics effective against AMR are more expensive and not affordable for many patients

• Increasing use of antibiotics with efficacy against AMR leads to higher resistance to “last-line” antibiotics

  • In fact, carbapenem consumption is increasing at a rapid pace in poor economies.⁸
    

• Lack of access to antibiotics in some poorer countries, a driver of mortality particularly in children under 5 years of age;
• Lack of access to newer, expensive antibiotics needed to treat the increasing toll of MDR and XDR bacterial infections;
• Inequity in ability to provide the basic public health interventions that drive many of the social determinants of infectious diseases in LMICs

The singular effectiveness of access to clean water, sanitation and hygiene, called WASH, in preventing the spread of disease is well understood, yet billions of people around the world still lack access to these necessities.⁹

• Currently, 2.1 billion people live without access to safe drinking water and 4.5 billion people are without access to adequate sanitation.
• Every day, 1300 children under 5 die from preventable diarrhoeal diseases, including cholera, caused by contaminated water and poor sanitation.
• 1 in 3 healthcare facilities lacks soap and water or hand sanitizer where staff provide patient care. Billions of patients worldwide must rely on these facilities.
• In some countries, up to 90% of women receive routine prophylactic antibiotics during childbirth, highlighting the conditions under which they are delivering their babies and what would cause the inevitability of infection

The cumulative lack of WASH adds up to children and adults not only getting unnecessarily sick—with the associated suffering, medical costs and loss of income or schooling—they are relying on antibiotics to get better.¹⁰ The challenge here is that WASH is a public works solution for a public health problem. WASH is not a pill or ‘quick fix’. It requires capital investment, system strengthening, and behaviour change to ensure that clean water and functional toilets are available and utilized day-in and day-out. These issues require a different set of skills than those possessed by medical and public health professionals.

In LMICs, an estimated 670 million people still practice open defaecation in 2017, and only one in three people have access to safe drinking water, resulting in high rates of diarrheal disease and equally large amounts of inappropriate antibiotic use.¹⁰ According to WHO surveys, vaccination, a cornerstone of infection prevention and reducing the need for antibiotic use, is suboptimal in both HICs and LMICs. In 2019, global third-dose coverage for childhood pneumococcal vaccination in 149 member states was only 48%, and global rotavirus vaccine coverage was estimated at 39%. In South Africa, middle-income country, procures less than 1 million doses of influenza vaccine for its annual influenza season, despite in excess of 10 million people being identified as high-risk for influenza and prioritized for vaccination.

Optimizing infection prevention on farms and making improvements to housing conditions and feed to reduce illness in animals is also critical in food production to offset the need for antibiotic growth promotion or metaphylaxis in food production animals. While there has been progress in the reduction of antibiotic use in farms in the EU and other HICs, attention nor funding for such improvements in LMICs has not even been proposed. “It’s one thing being told to reduce your antibiotic use in food production, it’s another to have the means to do so, even for the most committed resource-poor farmer.

As discussed above, the emergence of antimicrobial resistance (AMR) is a complex phenomenon and is intensified by selective pressure through antibiotic use in humans, animals, and agriculture. The transmission of AMR to humans occurs from contact with animals (including food), other humans, and the environment. Transmission is facilitated by several factors, including high population density, lack of access to clean water, suboptimal sewage systems, poor sanitation, and poor healthcare infection control practices, all of which are more common in LMICs. With the increasing consumption of antimicrobials in humans, lack of regulation on antimicrobial use in farming, and pharmaceutical industry pollution, it may not be surprising that relatively higher levels of AMR among human pathogens are being reported from LMIC.

The international focus on awareness, surveillance, infection prevention, stewardship and research and development (R&D) of new antibiotics is actually widening the equity gap by pouring millions of dollars into R&D of new antibiotics and surveillance systems, while the intervention that could benefit LMICs the most, infection prevention, has received a relatively few resources.

What are the possible solutions? Recently COVID-19 has refocused attention that in infectious diseases The Access to COVID-19 Tools (ACT)-Accelerator that we will discuss in Model 2 has shown that financial contributions from HICs to a LMIC-pool can improve equitable access to diagnostics, therapeutics and vaccines, but it is conceivable that the same model could be broadened to encompass tools that would support major social change for AMR.

AMR situation in Italy

Southern Europe, including Italy, has among the highest rates of resistance for pathogens included on the WHO Priority Pathogen list. For example, surveillance data from the European Centres for Disease Control (ECDC) have reported a dramatic increase in multidrug-resistance (MDR) in Italy since 2009, with now more than one-third of Klebsiella pneumoniae resistant to previously-considered last-line antibiotics such as carbapenems. An interactive ECDC resistance atlas showing differences in resistance rates between countries for common antibiotics can be found here. Similarly, the Italian Antimicrobial Surveillance system (Micronet Resistance Surveillance) has reported:

• 26.4% of Escherichia coli are resistant to 3rd generation cephalosporins
• 29.5% of Klebsiella pneumoniae are resistant to carbapenems (including 33.1% resistant to multiple drug classes)
• 15.9% of Pseudomonas aeruginosa are resistant to carbapenems
• 80.8% of Acinetobacter spp. are resistant to carbapenems with 78.8% of species resistant to multiple drug classes
• For the Gram-positive organism Staphylococcus aureus, the percentage of methicillin-resistant isolates (MRSA) remained stable, around 34%, while a worrying trend continues to increase in the percentage of Enterococcus faecium isolates resistant to vancomycin, which in 2020 was equal at 23.6%
• For Streptococcus pneumoniae there was a slight increase in both the percentage of isolates resistant to penicillin (13.6%) and those resistant to erythromycin (24.5%).
• Overall, higher antimicrobial resistance rates (around 40%) are observed in ICUs versus general medical wards for both carbapenem-resistant K. pneumoniae and methicillin-resistant S. aureus.

In 2017, a report by the the ECDC noted that the AMR situation in Italian hospitals and regions poses a major public health threat to the country. The levels of carbapenem-resistant Enterobacteriaceae (Enterobacterales) (CRE) and Acinetobacter baumannii have now reached hyperendemic levels in many hospitals. Together with increasing methicillin-resistance among the Gram-positive species Staphylococcus aureus (MRSA), these resistance trends has led to Italy’s ranking as one of the Member States with one of the highest level of antibiotic resistance in Europe. Factors noted by the ECDC that contributed negatively to the poor control of antibiotic resistance in Italy include:

• Little sense of urgency about the current AMR situation from most stakeholders and a tendency by many stakeholders to avoid taking charge of the problem
• Lack of institutional support at national, regional and local level
• Lack of professional leadership at each level
• Lack of accountability at each level
• Lack of coordination of the activities between and within levels.

The global future of AMR

• Drug-resistant infections already cause at least 700,000 deaths globally a year, including 230,000 deaths from multidrug-resistant tuberculosis. The estimated total number of deaths due to AMR could climb to 10 million deaths globally per year by 2050 under current projections.
• Increasing resistance could lead to an unthinkable future of untreatable infections, reversing more than a 100 years of medical progress. Routine medical procedures or surgery will become more dangerous and associated with higher complication rates. Immunosuppression, cancer chemotherapy and transplantation may carry unacceptable risk for many patients if infections cannot be effectively prevented and treated.
• Economic and social progress in many countries will be dramatically impacted by increasing AMR leading to political and social instability. The initial short-term economic damage of uncontrolled antimicrobial resistance will be comparable to the economic shocks experienced during the 2008-2009 global financial crisis and result in dramatically-increased healthcare expenditures; reductions in food and feed production, reduced economic output, and increased poverty and inequality. The economic impact of antimicrobial resistance is predicted to be even greater and longer lasting on low-and middle-income (LMIC) countries.

One-Health Perspective of AMR

Because the drivers of antimicrobial resistance lie in humans, animals, plants, food and the environment, a sustained One Health response is essential to engage and unite all health and environmental sectors around a shared vision and goals. “One Health” refers to designing and implementing programmes, policies, legislation and research in a way that enables multiple groups engaged in human, terrestrial and aquatic animal and plant health, food and feed production and the environment to communicate and work together to achieve better public health outcomes.

Cross-border spread of AMR

The COVID-19 pandemic has exposed the limitations of global collaboration and response within existing global health frameworks, pointing to a clear need for more rules-based global governance to be able to effectively prevent, prepare and respond to health emergencies in a more just equitable way. However, valuable lessons from COVID-19 pandemic could enhance actions against AMR. (Table 1.2). Clearly, actions taken by one country have had substantial consequences for others. governments should significantly bolster global and national capacity to prevent and respond to global cross-border health threats more broadly.

The actions of the EU during the pandemic illustrate the tension between short-term nationalistic incentives and long-term imperatives for cooperation towards achieving global public goods such as reducing antimicrobial resistance. The EU has struggled to balance preferences of individual member-states (and those of their political leaderships), with the collective interests of all member-states. Such tensions are especially challenging when health care and health policy issues are involved, given how these have hitherto remained largely the responsibility of the member-states. In a pandemic, this can lead to inertia and political indecisiveness at the EU level, with member-states filling the gap with potentially contradictory or competing decisions.

Looking ahead, it is likely that there will be several changes to the global health architecture, possibly including a new pandemic treaty and additional international collaborative mechanisms to promote preparedness and coordinate responses. In the following sections, we explore what those developments might look like in three key areas.

Summary

The post-COVID-19 world must overcome the serious setbacks from the pandemic to hard-fought progress in reducing poverty and inequality. Health infrastructure and human resources vital for fighting AMR have been overburdened and will take many years to recover, particularly if governments impose austerity measures as they seek to recover from fiscal expansion during the pandemic.

Decades of funding neglect, combined with continuously increasing global antibiotic consumption, poor surveillance data, and weak pipelines for new drugs, vaccines and diagnostics, has left the world dangerously vulnerable to a pandemic of resistant and untreatable infections.

Therefore, strong multilateral collaboration is essential for the world to absorb these shocks and refocus on the silent but growing pandemic of AMR. Pandemics are opportunities to re-imagine governance structures and learn from previous experiences. COVID-19 has shown the importance of multilateral collaboration in diverse areas, including research and knowledge sharing, discovery, development and distribution of vaccines and medicines and access to diagnostics and medicines. Action is needed now to reverse the unthinkable future of untreatable infections.

Lecture Slides

References